Heterocyclic polynuclear keto alkenoic acids and the production thereof



the copendin'g' application of myselfand John M.

Patented July 22, l952 nmmccrctrc .POLXNUCLEAR KETO ALKENOIC. ACIDS AND THE PR-O- IDUCTIONJTHEREOF "lZ'CIaims. (outse -327) alcoholic solutionof the acid with an alcoholic solution of alkali. The salts are often insoluble in the-alcohol and may be obtained as precipitates. In other cases another solvent such as other or benzene may be added to throw down the salt. Salts of aliphatic amines may be obtained by treating a solution of the acid in an sents a. bivalent aliphatic hydrocarbon radical, organic solvent with a solution of the amine in and X represents hydrogem'alkyl oraralkylr'adiv, a similar solvent and precipitating the desiredcals, or cations derived from inorganic or organic l salt with another miscible solvent in which the bases. salt .isinsoluble.

.This application is a continuation-in-part of 1 I 'l his invention relates to aliphatic keto acids andl'derivativesjthereof substituted olyevcu aromatc' hetero; yclic radicals, and to" processes Iorj'theproduction thereof, In particularit lates to c ompou ds having the .generalfform'jula '5 TA #QQ= QQ w re n: A re en s a polycyclic aromatic heterocyclic radical, Rrepre '.,The un saturatedacids to which this invention I relatesv can be produced by halogenatinga. keto Brown',QSeria1-.;No. 772,456,, filed September .5, a d o the aI Q0H 1947,, now, U. S. Patent No 80,220, issued 5' wherein'Ar hasthe meaning iven hereinab v Au ust 30,1949. I r and nf'is an integer greater than 1 and not greater The compounds which compr e this invention tha and dehydrohalogenating t re ultin are useful as' therape'utid'agent's. "They are in kt9 .h&l h 'qO cids wh ch arcstart' general choleretic. agents and as such afl'ectjhe lu materials these pr sses are, Obtained flow of bile. Theyare' also antimetabolites-for 'as disclosed in the Burtner .and Brownflapplicm certain bacteria. In the forinfof 'saltsithese' acids ti n-S l 72.4 6, fi1e d Sep em er] 19 arejsolublein water and. niay beladministered Th l e b is iedo it i e t by a parente'ral' routeQf 1 the. form of fle dds vent such as a halogenated hydrocarbon, a satug or esters orQsalts they. may sbcfadn inistered rated hydrocarbon for .a lower alk'anfoic acid. orally. I l' Among the halogenating agents which are'suit In theforeg oinggeneral formula the polycyclic a are h n bromine. ulf r l hlori aromatic heterocyclii:- radical represented by Ar yl b e, iodine. chlorid N- i chosen from ,the radicals derived-from polycinimide, N -bromoacetamide, and the like. Prenuclear substances which are ar mati i h ferred dehydrohalogenating agents are weak 'acter and 'which' include xantheneythioxanth 36 bases such as alkali metal salts of lower alkanoic acids, as for example sodium or acetate.

phenoxthin and thianthrene. The'biv'a'lent' radi cal, R, is an aliphaticiadical derived from an 7 .1 z aliphatic hydrocarbon, which may be saturated My invention is fu disclosed y meta-1150f or unsaturated. The grouping R include 1 a the following examples, which are set forth for kylene radicals of 1E carbon atoms such as hBP DO of illustration and which in O Y methylene, ethylene, propylene, trimethylene, are 130.138 construed as limiting the; invention in butylene, tetramethylene, 'hexamethylene' -and P 't' in o It Willbe apparent-t0 those octamethylene, wherein the hydrocarbon ai skilled in the art'that innumerable conventional may be straight or branched. It further includes modifications in solvent, temperature, catalyst radicals derived from unsaturated hydrocarbons 40 an reagents can be adopted Without departure such as those derived from olefins such as ethylfrom the intent a d P pos Of h e t ene, propylene and butylene, and from acetylenes and related unsaturated aliphatic hydrocarbons. Example 1 Among the derivatives of keto acids correspond- A. Toa solution of 29.8 parts of 7-(2-thi0X- ing to the foregoing general formula, which are is anthene) oxobutyric acid in 350 parts of glawlthln the purview of this invention, are salts cial acetic acid at 60 C. is added'with good agitaof alkali and alkaline earth metals, salts of alition over a period of about 1 hour a solution of phatic amines and esters of aliphatic and arali- 16 parts of bromine in parts of glacial acetic phatic alcohols such as the methyl, ethyl, propyl, acid. The mixtureis agitated at about C. benzyl and related alcohols. Alkaline salts of 60 for /2 hour longer. Then about 80% of the these acids may be prepared by solution of the solvent is removed by evaporation under reduced acid in an alkaline carbonate solution, such as pressure. The residue is diluted with 250 parts sodium carbonate, followed by salting-out with of petroleum ether and chilled. The precipitate a salt, as forfexample sodium chloride. Likewise (if 'r-(z-thioxanthene) *Y- -B- -W such salts may be prepared by treatment of an acid is separated and dried.,

sa e -su agitated for about 1 hour.

v 3 v B. A solution of 33 parts of the foregoin bromo acid and 6 parts ofiused sodium acetate in 110 parts of glacial acetic acid is refluxed and The hot mixture is poured into, 1Q0.0parts. of iceand water. The precipitate l of y-iY-ijhioxanthene) yjOXQCI'QtOIliC acid is separated, washed well with water and dried at 60-65 C. It has the formula tyric acid are brominated as in part A above with 16 parts of bromine.

Theresultingy-(Q-g Y thianthrene) -7 0x0 S- bromobutyric acid" (34:;

parts) is refluxed with 6 parts of fused sodium acetate in glacial acetic acid as in part B above.

The hot mixture is poured into a large volume of i e waterand the precipitate of 'v-(2-thi'an- Y Emample'z A 15. parts of "y-(zrphfil'loxthil'l)-"y-OXO bl1ty1iC ac d, 'arejbrominated in 150 vparts of acetic acid with. a solution of 8 parts oibromirie in 25 parts 9 jacetic acid,..according to the methodof. EX-

v I V fy-(z- -pllelloxthin).-'Y-OXQ?fi-bITOIIlOf butyricacid ineltsiat about'173' C. (with decomp si j lir 1 'B'," slolutior' fof 16 parts of. "y- (-2-ph'enoxthinl Yz'Q .ebr'omobutyric acid and 5.8 partsoifused threne) "-'y oxocrotoni'c'acid is separated, washed kip sodium acetate in. 50 parts'of acetic acid is .re-E

ijuxedjlfor '40 minutes. I'he unsaturated acidlis isolated'asjin'EXample, lB. After recrystallizar tion, from. acetic acid v-(2-phen0xthir'1). -oxo crjdfionic acid melts at about lQOF-C. It has the formula. I r

i lemma 1 l compound having the formula I ArCO-R-- 'cIooX iv whereinAr isa monovalentradical'o'f a polynucleararomatic heterocyclic compound selected from the group consisting of xanthene, thiox'ari thene,r henoxthin and thianthrene. R is-a, bi

c. 31.4 parts of -(2-thianthr'ne)' woxob m valent olefini cjhydroca'rloon radical, and X is a 7 member of the group consisting of hydrogen, alkyl radicals and cations. V

2. A compound as in claim 1 wherein R is a vbivalent.olefinic radical; I is j laim ljw erein R is a vinylene radical.

@ v 4. 'y Thioxanthene 'y oxocrotonic acid and V salts thereof.

' 5. 'y Thianthrene-'y oxocrotonic acid and salts 6. 'y-Pheno'xthin-y-oxocrotonic acid and salts .thereoi,

1. 1-0 The process of producing a compound as in claim 1 which comprises 'halogenating an acid of the formula I Ar-CO-R'-COOH wherein .Ar', is? p nuclear. aromatic heterocyclic, compound selected iro 'm; the group consisting of "'i'ran'th ena thickanthen, phenoxthin and thianthren e,fand R is a biyalentfsaturated aliphatic. hydrocarbon radicaLQa'nd "subsequently: fdehydrohalogenating the resulting halogenated ma;-

ll. The processjof ,prodcing a rijacid" of uije iormula, 1 V i. Ar-COCH=CHCOOl-l wherein Ar is'a monovalentyradicallofia poly: nuclear aromatic heterocyclic compound selected from the group consisting of xanthene, thiox anthene, 'phen'oxthin and thianthrene, which comprises halog enatir g an acid' oi the formula sultinghalogenated acid.

and subsequently dehydrohalogenatin g thre-'- l2. ";lhe processfof producing 'y-phe 'iQXPhin y oxo'c'rotonic acid which comprises halogenating "y phenoirthin- -oxobutyric acid and' dehydro halogenating the resulting halogenated acid with an alkali metal loweralkanoate.

' R B B RBU TNE r'tE RaNeEscIT D M V The following references. are of record in .the

file oifthispatent: p V p UNITED STATES PATENTS" Number T-Na'ri e" I l Date 2,4f i0 2 20 Burtn'er Aug. 30, 1949 QO'ljI-IER REFERENCES Weygan'd'i' Organic Preparations; pp. 79- and 422,'Inter-Science Pub'L, N-.Y. 1945. I

fmonoylalentfradi cal 6f $3561 

1. A COMPOUND HAVING THE FORMULA 